Hydrochloric Acid → 2-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)nicotinic acid

Participants

Reaction Conditions

Reaction Steps

To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.10 g, 0.42 mmol, Compound C of Example 1) and 2-fluoronicotinic acid (Aldrich, 0.084 g, 0.59 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.42 mL, 1.7 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W). The temperature was measured with an IR temperature sensor and maintained at 120° C. for two hours followed by 140° C. for six hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to afford the desired compound (0.13 g, 82%) as an off-white solid. 1H NMR (DMSO-d6) δ 13.75 (br s, 1H), 12.11 (s, 1H), 10.60 (s, 1H), 8.40 (dd, 1H, J=4.7, 1.9 Hz), 8.24 (dd, 1H, J=7.7, 1.9 Hz), 8.10-8.20 (m, 2H), 7.30-7.49 (m, 3H), 6.90 (dd, 1H, J=7.7, 4.8 Hz), 6.48 (d, 1H, J=5.8 Hz), 6.31-6.40 (m, 1H); HRMS(ESI+), 365.1050 (M+H)+ calc, 365.1038 (M+H)+ found.

Provenance & Evidence